Erythromycin A derivatives and method for preparing same

ABSTRACT

Erythromycin A derivatives represented by the general formula 
                 
 
wherein R 1  is a 2-alkenyl group having 3 to 15 carbon atoms, an arylmethyl group, or an arylmethyl group substituted by 1 to 3 of a halogen atom, an alkoxy group 1 to 4 carbon atoms, a nitro group or an alkoxycarbonyl group having 2 to 6 carbon atoms, R 2  is a substituted silyl group and R 3  is a hydrogen atom or R 2 , are disclosed. These compounds are useful as intermediates of the anti-bacterial agents.

This application is a continuation, of application Ser. No. 07/094,888,filed Sep. 10, 1987 now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to erythromycin A derivatives and themethod for the preparation of the same.

2. Description of the Prior Art

6-O-Methylerythromycins are useful as anti-bacterial agents orintermediates for synthesis of the antibacterial agents. For example,6-O-methylerythromycin A is not only stable under the acidic conditionsbut also has a strong antibacterial activity when compared witherythromycin A. Especially, this compound shows an excellent effect fortreatment of infections by oral administration, and therefore it is auseful antibacterial agent.

There are known in the past some methods for methylating the hydroxygroup at the 6-position of the erythromycin A derivatives, for example,(1) a method which comprises substituting the hydrogen atom of thehydroxy group at the 2′-position and the methyl group of thedimethylamino group at the 3′-position of the erythromycin A derivativesby benzyloxycarbonyl groups, and then methylating the resulting compound(U.S. Pat. No. 4,331,803), and (2) a method which comprises convertingerythromycin A derivatives having the protected hydroxy group at the2′-position and/or the protected dimethylamino group at the 3′-positioninto the various kind of the substituted oxime derivative, and thenmethylating the substituted derivatives (European Patent 158,467).

However, since erythromycin A has many hydroxy groups, there areobtained various kind of erythromycin A derivatives which are methylatedat hydroxy groups at any other than the 6-position as the by-products bythe method of item (1). Accordingly, this method requires thecomplicated procedure for purification of the 6-O-methylerythromycin Aderivatives, and has drawback of causing low yield of said derivatives.Although it is possible to methylate selectively the 6-hydroxy group bythe method of item (2), when the erythromycin A 9-oxime derivative whose2′-hydroxy group only is protected is methylated, the 3′-dimethylaminogroup is changed to a methyl quaternary salt under ordinary methylationconditions. Furthermore it is difficult to return the salt to adimethylamino group, accordingly, it is necessary to protect both of the2′-hydroxy group and 3′-dimethylamino group for the practicalpreparation method.

SUMMARY OF THE INVENTION

As a result of the various researches to solve the drawbacks of theabove known methods, the present inventors have found the fact thaterythromycin A derivative whose 2′-hydroxy group is protected with thesubstituted silyl groups is not quaternarized at the adjacent3′-dimethylamino group even under ordinary methylation conditions, andthe present invention has been completed.

DETAILED DESCRIPTION OF THE INVENTION

An object of the present invention is to provide 6-O-methylerythromycinA derivatives represented by the general formula

wherein R¹ is a 2-alkenyl group having 3 to 15 carbon atoms, anarylmethyl group, or an arylmethyl group substituted by 1 to 3 of ahalogen atom, an alkoxy group having 1 to 4 carbon atoms, a nitro groupor an alkoxycarbonyl group having 2 to 6 carbon atoms, R² is asubstituted silyl group of formula —SiR⁴R⁵R⁶ (wherein R⁴, R⁵ and R⁶ arethe same or different, and each is a hydrogen atom, an alkyl grouphaving 1 to 15 carbon atoms, a phenyl substituted alkyl group in whichthe alkyl moiety has 1 to 3 carbon atoms, a phenyl group, a cycloalkylgroup having 5 to 7 carbon atoms or an alkenyl group having 2 to 5carbon atoms, with the proviso that at least one of R⁴, R⁵ and R⁶ isother than hydrogen atom) and R³ is a hydrogen atom or R².

Another object of the present invention is to provide erythromycin Aderivatives represented by the general formula

wherein R¹, R² and R³ are as defined above.

Still another object of the present invention is to provide a method forpreparing 6-O-methylerythromycin A derivatives of formula I whichcomprises reacting, in any desired sequence, erythromycin A 9-oxime witha compound of formula R¹—X (wherein R¹ is as defined above, and X is ahalogen atom) and with a substituted silylating agent having R² group togive a compound of formula II, and then reacting the compound of formulaII with a methylating agent.

In the present invention, the terms “alkyl”, “alkoxy” and “alkenyl” usedalone or as combined with the other group mean those whose carbon chainmay be linear or branched. The term “arylmethyl group” means a benzylgroup, a benzhydryl group, a trityl group or a naphthylmethyl group.Examples of the substituted arylmethyl group are a p-methoxybenzylgroup, a p-chlorobenzyl group, a m-chlorobenzyl group, o-chlorobenzylgroup, a 2,4-dichlorobenzyl group, a p-bromobenzyl group, am-nitrobenzyl group, a p-nitrobenzyl group and the like. Examples of2-alkenyl group for R¹ are an allyl group, a methallyl group, a crotylgroup, a prenyl group, a 2-pentenyl group, a 2-ethyl-2-butenyl group, ageranyl group, a neryl group and the like. The term “halogen atom”refers to a chlorine, a bromine, an iodine atom and the like. Examplesof the substituted silyl group are a timethylsilyl group, atriethylsilyl group, an isopropyldimethylsilyl group, atert-butyldimethylsilyl group, a (triphenylmethyl)dimethylsilyl group, atert-butyldiphenylsilyl group, a diphenylmethylsilyl group, adiphenylvinylsilyl group, a methyldiisopropylsilyl group, atribenzylsilyl group, a tri(p-xyryl)silyl group, a triphenylsilyl group,a diphenylsilyl group, a dimethyloctadecylsilyl group and the like.

The present invention is illustrated below in more detail. At first,etherification of erythyromycin A 9-oxime with a compound of formulaR¹—X is carried out according to the known method per se, for example,the method described in European Patent No. 158,467 to give a compoundof formula

wherein R¹ is as defined above.

The reaction of the compound of formula III with the silylating agent iscarried out in a solvent in the presence of a base at 0° C. to thereflux temperature of the solvent, preferably at room temperature withstirring. Examples of the silylating agent used are chlorosilanes suchas trimethylchlorosilane, tert-butyldimethylchlorosilane and the like;silylamines such as 1,1,1,3,3,3-hexamethyldisilazane,trimethylsilylimidazole, dimethylaminotrimethylsilane and the like;bis(trimethylsilyl)acetamide, trimethylsilydiphenylurea,bis(trimethylsilyl)urea and the like. The amount of the silylating agentused is 1 to 10 equivalents, preferably 1 to 5 equivalents relative tothe compound of formula III.

Examples of the solvent used in the reaction are acetone,tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, dioxane,1,2-dimethoxyethane, dichloromethane, chloroform and the like. Examplesof the base are inorganic bases such as sodium hydroxide, potassiumhydroxide, potassium carbonate, sodium bicarbonate, potassiumbicarbonate and the like; and organic bases such as trimethylamine,triethylamine, pyridine, 1,8-diaza-bicyclo [5,4,0]unde-7-cene, imidazoleand the like.

Although difference of the silylation at the 2-position only betweenboth of the 2′- and 4″-positions of the compound of formula III dependson the reaction conditions, it is preferable to use a chlorosilane forthe silylation at the 2-position only, and it is preferable to use botha chlorosilane and a silylamine or 1,1,1,3,3,3-hexamethyldisilazane forthe silylation at the 2′- and 4″-positions.

Alternatively, the compound of formula II can be obtained byetherification after silylation of erythromycin A 9-oxime. Namely,erythromycin A 9-oxime is reacted with the silylating agent under thesame silylation conditions as described above, and then the resultingcompound is reacted with the compound of formula R³—X under the sameetherification conditions as described above to give the compound offormula II.

The reaction of the compound of formula II with the methylating agentfor preparing the compound I can be carried out in a solvent in thepresence of a base at −15° C. to room temperature, preferably at 0° C.to room temperature with stirring. Examples of the methylating agent aremethyl bromide, methyl iodide, dimethyl sulfate, methylp-toluenesulfonate, methyl methanesulfonate and the like. It issufficient to use 1-3 molar equivalents of the methylating agentrelative to the compound of formula II. Examples of the solvent used arepolar aprotic solvent such as N,N-dimethylformamide, dimethyl sulfoxide,N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereofor a mixture of one of these solvents and a solvent such astetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate or thelike. Examples of the base are sodium hydroxide, potassium hydroxide,sodium hydride, potassium t-butoxide, potassium hydride and the like.The amount of the base used is usually 1-2 molar equivalents relative tothe compound of formula II.

In order to prevent the quaternarization of the 3′-dimethylamino groupwhen the compound of formula II is methylated, it is essential toprotect the 2′-hydroxy group with the substituted silyl ether, but notnecessarily essential to etherify the 4″-hydroxy group with thesubstituted silyl group.

The compound of formula II may be used after isolation or withoutisolation for reacting with the methylating agent.

Although erythromycin A 9-oxime derivatives of the present inventionexist in two isomers (syn- and anti-forms), for the purpose of thepresent invention, these compounds may exist in either of the isomersand in a mixture thereof.

In the method for preparing the 6-O-methylerythromycin A derivatives ofthe present invention, it is not necessary to protect the3′-dimethylamino group, therefore, it is not necessary to carry out the3′-N-methylation, either.

The methylation of the hydroxy group at the 6-position of the presentinvention has good selectivity as well as the prior art method.Furthermore, the substituted silyl groups used for the protection of thehydroxy groups, at the 2′- and 4″-positions can be easily eliminated.

Therefore, the present invention can provide 6-O-methylerythromycin A inhigh yield and economically. Namely, the compound of formula I can beled to 6-O-methylerythromycin A, for example, by the following method.

The elimination of the substituted silyl groups (R² and R³) at the 2′-and 4″-positions of the compound of formula I can be carried out easilyby treatment with an acid (e.g., formic acid) in an alcohol or withtetrabutyl ammoniumfluoride in tetrahydrofuran.

The elmination of R¹ group of the resulting compound can be carried outby homogeneous or heterogeneous hydrogenolysis known per se. Forexample, this reaction may be carried out in an alcoholic solvent (e.g.,methanol, ethanol and the like) in the presence of a catalyst such aspalladium black or palladium carbon under a hydrogen atomosphere withstirring. The addition of formic acid, acetic acid or the like isconvenient for the progress of the reaction.

This reaction can also be carried out easily in the presence of asuitable hydrogen source (e.g., ammonium formate, sodium formate, and amixture of these formates and formic acid) and a catalyst (e.g.,palladium carbon, palladium black and the like) in an organic solvent(e.g., methanol, ethanol, N,N-dimethylformamide and the like) withstirring at room temperature to 70° C.

Furthermore, this reaction may be carried out by using a platinum groupcompound and a ligand as a catalyst. Examples of the platinum groupcompound are the salts or complexes of ruthenium, rhodium, palladium andplatinum, and examples of the ligand are phosphor compounds such astriphenylphosphine, tri-n-butylphosphine, triethylphosphite,1,2-ethylene(diphenyl)phosphine and the like. Usually, mixture ofpalladium acetate and triphenylphosphine may be used. This reaction canbe carried out in the presence of formic acid or a salt thereof.Examples of the salt of formic acid are ammonium salts thereof such asammonium formate, trimethylammonium formate, triethylammonium formateand the like, and alkali metal salts thereof such as sodium formate,potassium formate and the like.

The elimination procedure of R² and R³ and that of R¹ may be carried outin the reverse order without any trouble.

6-O-Methylerythromycin A 9-oxime thus obtained can be converted easilyto 6-O-methylerythromycin A by deoximation using sodium hydrogensulfite, titanium trichloride-ammonium acetate, sodiumnitrite-hydrochloric acid, sodium hydrosulfite (Na₂S₂O₄) and the like.

Next, the present invention will be concretely illustrated by Exampleswhich show the method for preparing the compound of formula I andReferential Examples which show the method for preparing6-O-methylerythromycin A.

EXAMPLE 1 Preparation of 2′-O-trimethylsilylerythromycin A9-(O-benzyloxime)

To a solution of 3.36 g of erythromycin A 9-(O-benzyloxime) and 0.7 mlof triethylamine in 30 ml of N,N-demthylformamide was added dropwse atroom temperature 0.7 ml of trimethylchlorosilane, and the mixture wasstirred for 10 minutes. To the reaction solution was added isopropylether, and the mixture was washed with, in turn, water and a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the resulting crude product wasrecrystallized from isopropyl ether to give 1.35 g of the title compoundas colorless needles.

-   -   m.p. 104-106° C.    -   Mass(FAB); m/z: 911(MH⁺)    -   PMR(CDCl₃)    -   δ (ppm)=0.11(2′-O-TMS), 2.23[3′N(CH₃)₂], 3.33(3″-OCH₃)    -   CMR(CDCl₃)    -   δ (ppm)=1.0(2′-O-TMS), 41.0[3′-N(CH₃)₂], 49.5(3″-OCH₃)        (TMS as used above and hereinafter is a trimethylsilyl group)

EXAMPLE 2 Preparation of 2′,4″-O-bis(trimethylsilyl)erythromycin A9-(O-benzyloxime)

To a solution of 2.24 g of trimethylsilylimidazole and 1.74 g oftrimethylchlorosilane in 20 ml of dry dichloromethane was added at onceat room temperature a solution of 6.72 g of erythromycin A9-(O-benyzloxime) in 40 ml of dichloromethane, and the mixture wasstirred at room temperature for 10 minutes. Chloroform was added, andthe mixture was washed with, in turn, water and a saturated aqueoussodium chloride solution and drived over anhydrous magnesium sulfate.The solvent was evaporated and the resulting crude product wasrecrystallized from acetone-water to give 5.27 g of the title compoundas colorless needles.

-   -   m.p. 97-100° C.    -   Mass(FAB); m/z: 983(MH⁺)    -   PMR(CDCl₃)    -   δ (ppm)=0.09(2′-O-TMS), 0.15(4″-O-TMS), 2.22[3′-N (CH₃)₂],        3.31(3″-OCH₃)    -   CMR(CDCl₃);    -   δ (ppm) =0.9(4″-O-TMS), 1.0(2′-O-TMS), 41.0[3′-N (CH₃)₂],        49.7(3″-OCH₃)

EXAMPLE 3 Preparation of 2′-O-trimethylsilyl-6-O-methylerythromycin A9-(O-benzyloxime)

To a solution of 2.28 g of 2′-O-trmethylsilylerythromycin A9-(O-benzyloxime) in 20 ml of a mixture of dimethyl sulfoxide andtetrahydrofuran (1:1) were added 0.38 ml methyl iodide and 280 mg of 85%potassium hydroxide powder, and the mixture was stirred at roomtemperature for 2 hours. To the reaction solution was added ethylacetate, and the mixture was washed with, in turn, water and a saturatedaqueous sodium chloride solution, and dried over anhydrous magnesiumsulfate. The solvent was evaporated to give 2.32 g of the glassy titlecompound.

-   -   Mass(FAB); m/z: 925(MH⁺)    -   PMR(CDCl₃)    -   δ (ppm)=0.09(2′-O-TMS), 2.23[3′-N(CH₃)₂], 3.03(6-OCH₃),        3.34(3″-OCH₃)

EXAMPLE 4 Preparation of2,4″-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-(O-benzyloxime)

Treating 3.93 g of 2′,4″-O-bis(trimethylsilyl) erythromycin A9-(benzyloxime) according to the procedure similar to that of Example 3,there was obtained 3.89 g of the glassy title compound.

-   -   m.p. 115-116° C. (recrystallized from methanol)    -   Mass(FAB); m/z: 997(MH⁺)    -   PMR(CDCl₃)    -   δ (ppm)=0.09(2′-O-TMS), 0.15(4″-O-TMS), 2.21[3′-N (CH₃)₂],        3.03(6-OCH₃), 3.23(3″-OCH₃)    -   CMR(CDCl₃)    -   δ (ppm)=0.9(4″-O-TMS), 1.1(2′-OCH₃), 41.0[3′-N(CH₃)₂],        49.7(3″-OCH₃), 50.7(6-OCH₃)

EXAMPLE 5 Preparation of 2′-O-trimethylsilylerythromycin A9-(O-allyloxime)

Treating 1 g of erythromycin A 9-(O-allyloxime) according to theprocedure similar to that of Example 1, there was obtained the crudeproduct, which was then purified by alumina column chromatography(eluent; acetone/n-hexane=1/10-1/5) to give 0.35 g of the glassy titlecompound.

-   -   m.p. 93-96° C. (recrystallized from n-hexane)    -   Mass(EI); m/z: 860(M⁺)    -   PMR(CDCl₃)    -   δ (ppm)=0.11(2′-O-TMS), 2.23[3′-N(CH₃)₂], 3.32(3″-OCH₃)    -   CMR(CDCl₃)    -   δ (ppm)=1.0(2′-O-TMS), 41.0[3′-N(CH₃)₂], 49.5(3″-OCH₃)

EXAMPLE 6 Preparation of 2′,4″-O-bis(trimethylsilyl) erythromycin A9-(O-allyloxime)

Allowing to react 1 g of erythromycin A 9-(O-allyloxime) according tothe procedure similar to that of Example 2, and then 100 ml of n-hexanewas added to the reaction solution. The insoluble was filtered off, andthe filtrate was concentrated. The residue was purified by silica gelcolumn chromatography (eluent; acetone/n-hexane/triethylamine=1/10/0.1)to give 0.70 g of the glassy title compound.

-   -   m.p. 85-89° C. (recrystallized from acetone)    -   Mass(EI); m/z: 932(M⁺)    -   PMR(CDCl₃)    -   δ (ppm)=0.10(2′-O-TMS), 0.14(4″-O-TMS), 2.22[3′-N (CH₃)₂],        3.31(3″-OCH₃)

EXAMPLE 7 Preparation of 2′-O-trimethylsilyl-6-O-methylerythromycin A9-(O-allyloxime)

To a solution of 4 g of erythromycin A 9-(O-allyloxime) and 1.4 ml oftriethylamine in 20 ml of N,N-dimethylformamide was added dropwise atroom temperature 1.35 ml of trimethylchlorosilane, and the mixture wasstirred for 20 minutes, 100 ml of water was added, and the mixture wasextracted with ethyl ether. The organic layer was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate. The solvent was evaporated to give 3.86 g of thecrude product of 2′-O-trimethylsilyerythromycin A 9-(O-allyloxime).

To a solution of the above compound in 30 ml of a mixture of dimethylsulfoxide and tetrahydrofuran (1:1), were added under ice-cooling 0.42ml of methyl iodide and then 357 mg of 85% sodium hydroxide powder, andthe mixture was stirred for 1.5 hours. After completion of the reaction,0.5 ml of 50% aqueous dimethylamine solution was added, and the mixturewas stirred for an hour. 100 ml of water was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate. The solvent was evaporated, and the residue waspurified by silica gel column chromatography (eluent;acetone/n-hexane/triethylamine=1/5/0.1) to give 1.45 g of the glassytitle compound.

-   -   m.p. 155-158° C. (recrystallized from n-hexane)    -   Mass(EI); m/z: 874(M⁺)    -   PMR(CDCl₃)    -   δ (ppm)=0.10(2′-O-TMS), 2.22[3′-N(CH₃)₂], 3.08(6-OCH₃),        3.33(3″-OCH₃)    -   CMR(CDCl₃)    -   δ (ppm)=1.1(2′-O-TMS), 41.0[3′-N(CH₃)₂], 49.4(3″-OCH₃),        50.9(6-OCH₃)

EXAMPLE 8 Preparation of2′,4″-O-bis(trimethylsily)-6-O-methylerythromycin A 9-(O-allyloxime)

To a solution of 3.51 ml of trimethylsilylimidazole and 3.04 ml oftrimethylchlorosilane in 25 ml of dry dichloromethane was added at onceat room temperature a solution of 9.5 g of erythromycin A9-(O-allyloxime) in 125 ml of dichloromethane, and the mixture wasstirred at room temperature for 10 minutes. To the reaction solution wasadded 400 ml of n-hexane, the insoluble was filtered off, and thefiltrate was concentrated. To the residue was added 200 ml of n-hexane,the resulting insoluble was filtered off, and the filtrate wasconcentrated. To a solution of the residue in 75 ml of a mixture ofdimethyl sulfoxide and tetrahydrofuran (1:1) were added underice-cooling 1 ml of methyl iodide and then 854 mg of 85% potassiumhydroxide powder, and the mixture was stirred for 1.5 hours. Aftercompletion of the reaction, the treatment similar to that of Example 7gave 10.2 g of the title compound.

-   -   m.p. 96-101° C. (recrystallized from acetone-water)    -   Mass(EI); m/z: 946(M⁺)    -   PMR(CDCl₃)    -   δ (ppm)=0.09(2′-O-TMS), 0.15(4″-O-TMS), 2.22[3′-N (CH₃)₂],        3.09(6-OCH₃), 3.32(3″-OCH₃)    -   CMR(CDCl₃)    -   δ (ppm)=0.9(6-O-TMS), 1.1(2′-O-TMS), 41.0[3′-N(CH₃)₂],        49.7(3″-OCH₃), 50.9(6-OCH₃)

EXAMPLE 9 Preparation of2′,4″-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-(O-allyloxime)from erythromycin A 9-oxime

To a solution of 10 g of erythromycin A 9-oxime in 75 ml oftetrahydrofuran were added 1.25 ml of allyl bromide and 970 mg of 85%potassium hydroxide powder, and the mixture was stirred at roomtemperature for 2 hours. To the reaction solution was added 1 ml of 50%aqueous dimethylamine solution, and the mixture was stirred for 30minutes, poured into a mixture of methanol and water (50 ml: 200 ml) andstirred under ice-cooling for 30 minutes. The resulting precipitate wascollected by filtration, washed with water, dissolved in chloroform anddried over anhydrous magnesium sulfate. The solvent was evaporated togive 9.7 g of crude erythromycin A 9-(O-allyloxime).

To a solution of 3.58 ml of trimethylsilylimidazole and 3.10 ml oftrimethylchlorosilane in 25 ml of dry dichloromethane was added at onceat room temperature a solution of 9.7 g of erythromycin A9-(O-allyloxime), obtained above, in 125 ml of dichloromethane, and themixture was stirred at room temperature for 10 minutes. To the reactionsolution was added 200 ml of n-hexane, the resulting insoluble wasfiltered off, and the filtrate was concentrated. To the residue wasadded once more 200 ml of n-hexane, the insoluble was filtered off, andthe filtrate was concentrated to give 10 g of crude2′,4″-O-bis(trimethylsilyl) erythromycin A 9-(O-allyloxime).

To a solution of 10 g of crude 2′,4″-O-bis(trimethylsilyl) erythromycinA 9-(O-allyloxime), obtained above, in 75 ml of a mixture of dimethylsulfoxide and tetrahydrofuran (1:1) were added 1 ml of methyl iodide andthen 837 mg of 85% potassium hydroxide powder, and the mixture wasstirred under ice-cooling for 1.5 hours. After completion of thereaction, 1 ml of 50% aqueous dimethylamine solution was added, and themixture was stirred at room temperature for an hour. 200 ml of water wasadded, and the mixture was extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous sodium chloride solution andthen dried over anhydrous magnesium sulfate. The solvent was evaporatedto give 10.3 g of crude 2′,4″-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-(O-allyloxime). Purificationsimilar to that of Example 8 gave the title compound, which wasidentical with the compound obtained in Example 8 in terms of meltingpoint, and spectra of mass, PMR and CMR.

EXAMPLE 10 Preparation of 2′,4″-O-bis(trimethylsilyl) erythromycin A9-(O-benzyloxime) from erythromycin A 9-oxime

To a solution of 3.79 g of erythromycin 9-oxime and 0.75 ml of benzylchloride in 30 ml of N,N-dimethylformamide was added under ice-cooling0.24 g of sodium hydride (60%). After stirring for 2 hours, 2.5 ml of1,1,1,3,3,3-hexamethyldisilazane and 0.99 g of pyridine hydrochloridewere added, and the mixture was stirred for a further 6 hours. Afterbeing allowed to stand overnight, the reaction solution was poured intowater, extracted with ethyl actate. The organic layer was washed anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe resulting crude product was recrystallized from an aqueous acetoneto give 3.0 g of the title compound, which was identical with thecompound obtained in Example 2 in terms of melting point and spectra ofmass and PMR.

EXAMPLE 11 Preparation of2′,4″-O-bis(trimethylsilyl)-6-O-methylerythromycin A9-[O-(o-chlorbenzyl)oxime]

-   (1) To a solution of 90 g of erythromycin A 9-oxime in 500 ml of    N,N-dimethylformamide were added 23.6 g of o-chlorobenzyl chloride    and 9.7 g of 85% potassium hydroxide powder, and the mixture was    stirred under ice-cooling for 30 minutes. After completion of the    reaction, the mixture was extracted with ethyl acetate, washed with,    in turn, water and a saturated aqueous sodium chloride solution and    dried over anhydrous magnesium sulfate. The solvent was evaporated    under reduced pressure to give 98 g of erythromycin A    9-[O-(o-chlorobenzyl)oxime].    -   m.p. 114-117° C. (recrystallized from n-hexane)-   (2) To a solution of 8.7 g of the above compound in 80 ml of ethyl    acetate was added a solution of 2.53 ml of trimethylchlorosilane and    2.8 g of trimethylsilylimidazole in 10 ml of ethyl acetate, and the    mixture was stirred at room temperature for an hour. To the mixture    was added n-hexane, and the mixture was washed with, in turn, water    and a saturated aqueous sodium chloride solution and dried over    anhydrous magnesium sulfate. The solvent was evaporated to give 9.78    g of glassy 2′,4″-O-bis (trimethylsilyl)erythromycin A    9-[O-(o-chlorobenzyl) oxime].    -   Mass(EI); m/z: 1016(M⁺)    -   PMR(CDCl₃)    -   δ (ppm)=0.10(2′-O-TMS), 0.15(4″-O-TMS), 2.23[3′-N (CH₃)₂],        3.30(3″-OCH₃)-   (3) To a solution of 5.09 g of 2′,4″-O-bis(trimethylsilyl)    erythromycin A 9-[O-(o-chlorobenzyl)oxime] in 100 ml of a mixture of    dimethyl sulfoxide and tetrahydrofuran (1:1) were added 0.41 ml of    methyl iodide and then 360 mg of 85% potassium hydroxide powder, and    then the mixture was stirred under ice-cooling for 1.5 hours. To the    reaction solution was added 2 ml of 50% aqueous dimethylamine    solution, and the stirring was continued for 30 minutes. Thereafter,    to the mixture was added with n-hexane, and the resulting solution    was washed with, in turn, water and a saturated aqueous sodium    chloride solution and dried over magnesium sulfate. The solvent was    evaporated under reduced pressure to give 4.3 g of the glassy title    compound.    -   Mass(EI); m/z: 1030(M⁺)    -   PMR(CDCl₃)    -   δ (ppm)=0.10(2′-O-TMS), 0.15(4″-O-TMS), 2.22[3′-N (CH₃)₂],        3.02(6-OCH₃), 3.32(3″-OCH₃)

EXAMPLE 12 Preparation of 2′,4″-O-bis(trimethylsilyl) erythromycin A9-[O-(o-chlorobenzyl)oxime] from erhtyromycin A9-[O-(o-chlorobenzyl)oxime]

To a solution of 15.27 g of erythromycin A 9-[O-(o-chlorobenzyl)oxime],obtained in Example 11(1), in 150 ml of N,N-dimethylformamide were added7.8 ml of 1,1,1,3,3,3-hexamethyldisilazane and 2.6 g of pyridinehydrochloride, and the mixture was stirred at room temperature for 3hours. The reaction solution was poured into water and extracted withethyl acetate, and the extract was washed with, in turn, water and asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure togive 14.5 g of the title compound, which was identical with the compoundobtained in Example 11(2) in terms of spectra of mass and PMR.

EXAMPLE 13 Preparation of 2′,4″-O-bis(trimethylsilyl) erythromycin A9-[O-(o-chlorobenzyl)oxime] from erythromycin A 9-oxime

To a solution of 3 g of erythromycin A 9-oxime in 15 ml ofN,N-dimethylformamide were added 0.773 g of o-chlorobenzyl chloride and0.192 g of 60% sodium hydride, and the mixture was stirred underice-cooling for 2 hours. After completion of the reaction, the mixturewas armed to room temperature. To the reaction mixture were added 1.69ml of 1,1,1,3,3,3-hexamethyldisilazane and 0.321 g of ammonium chloride,and the mixture was stirred at room temperature for 20 hours. To thereaction solution were added 50 ml of n-hexane and 100 ml of a saturatedaqueous sodium chloride solution, and the organic layer was washed witha saturated aqueous sodium chloride solution (100 ml×2) and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure to give 4.2 g of the title compound, which was identical withthe compound obtained in Example 11(2) in terms of spectra of mass andPMR.

Referential Example 1 Preparation of 6-O-methylerythromycin A from 2′,4″-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-(O-allyloxime)

To a solution of 10.3 g of crude2′,4″-O-bis-(trimethylsilyl)-6-O-methylerythromycin A 9-(O-allyloxime),obtained in Example 9, in 100 ml of methanol was added 6.2 ml of 99%formic acid, and the mixture was stirred at 50° C. for an hour. To thereaction solution was added 300 ml of water, and the mixture was madebasic with 2N aqueous sodium hydroxide solution and extracted with ethylacetate. The organic layer was washed with a saturated aqueous sodiumchloride solution and dried over anhydrous magnesium sulfate. Thesolvent was evaporated to give 8.93 g of crude 6-O-methylerythromycin A9-(O-allyloxime).

To a solution of 8.93 g of crude 6-O-methylerythromycin A9-(O-allyloxime), obtained above, in a mixture of 50 ml of dioxane and7.5 ml of water were added 89 mg of palladium acetate, 539 mg oftriphenyl phosphine and 9.7 g of triethylammonium formate, and themixture was refluxed for 30 minutes. After completion of the reaction,the solvent was evaporated under reduced pressue, 200 ml of diethylether was added, and the mixture was extracted with 10% acetic acid. Theacetic acid layer was washed with, in turn, diethyl ether and n-hexane,made basic with 5N-sodium hydroxide and extracted with ethyl acetate.The organic layer was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasevaporated to give 8.5 g of crude 6-O-methylerythromycin A 9-oxime.

To a solution of 8.5 g of 6-O-methylerythromycin A 9-oxime, obtainedabove, in a mixture of 40 ml of ethanol and 40 ml of water were added4.65 g of sodium hydrogen sulfite and 1 ml of 99% formic acid, and themixture was refluxed for 100 minutes. To the reaction solution was added130 ml of water, and the mixture was adjusted to pH about 9.5 with anaqueous sodium hydroxide solution and stirred under ice-cooling for anhour. The resulting precipitate was collected by filtration, washedthroughly with water, and recrystallized from ethanol to give 4.19 g of6-O-methylerhtyromycin A.

-   -   m.p. 223-225° C.

Referential Example 2 Preparation of 6-O-methylerythromycin A from 2′,4″-O-bis(trimethylsilyl)-6-O-methylerythromycin A9-[O-(o-chlorobenzyl)oxime]

To a solution of 2.8 g of crude2,4″-O-bis(trimethylsilyl)-6-O-methylerythromycin A9-[O-(o-chlorobenzyl)oxime], obtained in Example 12, in 30 ml ofmethanol were added 450 mg of 10% palladium carbon, 1.8 ml of formicacid and 300 mg of ammonium formate, and the mixture was stirred at 60°C. for 2 hours. The palladium catalyst was filtered off, and thefiltrate, after addition of 200 ml of water, was made basic with 2Naqueous sodium hydroxide solution. The precipitate which formed wascollected by filtration, washed with water and dried to give 1.7 g ofcrude 6-O-erythromycin A 9-oxime.

By reacting 6-O-erythromycin A 9-oxime thus obtained with sodiumhydrogen sulfite and 99% formic acid according to the procedure similarto that of Referential EXAMPLE 1, there was obtained 1.17 g of6-O-methylerythromycin A as crystals.

-   -   m.p. 223-225° C.

1. A process for preparing a 6-O-methylerythromycin A derivativerepresented by the formula:

wherein R¹ is: a 2-alkenyl group having 3 to 15 carbon atoms, a benzylgroup, or a benzyl group substitued substituted by 1 to 3 of a chlorineatom, an alkoxy group having 1 to 4 carbon atoms, a nitro group or analkoxycarbonyl group having 2 to 6 carbon atoms, and R² and R³ aretrimethylsilyl, which comprises reacting, in any desired sequence,erythromycin A 9-oxime with a compound of formula R¹—X (wherein R¹ is asdefined above, and X is a halogen atom) and with a substitutedsilylating agent having an R² group to give a compound represented bythe formula; :

(wherein R¹, R² and R₃ are as defined above), and then reacting saidcompound of formula II with a methylating agent selected from the groupconsisting of methyl bromide, methyl iodide, dimethyl sulfate, methylp-toluene sulfonate and methyl methane sulfonate, the amount of saidmethylating agent being 1-3 molar equivalents of said compound offormula II, said trimethylsilyl group (R²) protecting the 2′ hydroxylgroup against methylation and preventing the 3′-dimethylamino group frombeing quaternized with the methylating agent.
 2. A process for preparing6-O-methylerythromycin A comprising: reacting, in any desired sequence,erythromycin A 9 -oxime with a compound of formula R ¹ —X (wherein R ¹is as defined below, and X is a halogen atom) and with a substitutedsilylating agent having an R ² group to give a compound represented bythe formula:

wherein R ¹ is: a 2 -alkenyl group having 3 to 15 carbon atoms, a benzylgroup, or a benzyl group substituted by 1 to 3 of a chlorine atom, analkoxy group having 1 to 4 carbon atoms, a nitro group or analkoxycarbonyl group having 2 to 6 carbon atoms, and R ² and R ³ aretrimethylsilyl; then reacting said compound of formula II with amethylating agent selected from the group consisting of methyl bromide,methyl iodide, dimethyl sulfate, methyl p-toluene sulfonate and methylmethane sulfonate, the amount of said methylating agent being 1-3 molarequivalents of said compound of formula II, said trimethylsilyl group (R²) protecting the 2′ hydroxyl group against methylation and preventingthe 3 ′-dimethylamino group from being quaternized with the methylatingagent; then eliminating in any desired sequence the R ¹ , R ² , and R ³groups, wherein the elimination of R ¹ is performed by hydrogenolysis;and then, deoximating with a deoximating agent.
 3. A process forpreparing 6-O-methylerythromycin A comprising: reacting, in any desiredsequence, erythromycin A 9 -oxime with a compound of formula R ¹ —X(wherein R ¹ is as defined below, and X is a halogen atom) and with asubstituted silylating agent having an R ² group to give a compoundrepresented by the formula:

wherein R ¹ is: a 2 -alkenyl group having 3 to 15 carbon atoms, a benzylgroup, or a benzyl group substituted by 1 to 3 of a chlorine atom, analkoxy group having 1 to 4 carbon atoms, a nitro group or analkoxycarbonyl group having 2 to 6 carbon atoms, and R ² and R ³ aretrimethylsilyl; then reacting said compound of formula II with amethylating agent selected from the group consisting of methyl bromide,methyl iodide, dimethyl sulfate, methyl p-toluene sulfonate and methylmethane sulfonate, the amount of said methylating agent being 1-3 molarequivalents of said compound of formula II, said trimethylsilyl group (R²) protecting the 2′ hydroxyl group against methylation and preventingthe 3 ′-dimethylamino group from being quaternized with the methylatingagent; eliminating in any desired sequence the R ¹ , R ² , and R ³groups, wherein the elimination of R ² and R ³ is performed by treatmentwith acid in an alcohol; and then, deoximating with a deoximating agent.4. A process for preparing 6-O-methylerythromycin A comprising:reacting, in any desired sequence, erythromycin A 9 -oxime with acompound of formula R ¹ —X (wherein R ¹ is as defined below, and X is ahalogen atom) and with a substituted silylating agent having an R ²group to give a compound represented by the formula:

wherein R ¹ is: a 2 -alkenyl group having 3 to 15 carbon atoms, a benzylgroup, or a benzyl group substituted by 1 to 3 of a chlorine atom, analkoxy group having 1 to 4 carbon atoms, a nitro group or analkoxycarbonyl group having 2 to 6 carbon atoms, and R ² and R ³ aretrimethylsilyl; then reacting said compound of formula II with amethylating agent selected from the group consisting of methyl bromide,methyl iodide, dimethyl sulfate, methyl p-toluene sulfonate and methylmethane sulfonate, the amount of said methylating agent being 1-3 molarequivalents of said compound of formula II, said trimethylsilyl group (R²) protecting the 2′ hydroxyl group against methylation and preventingthe 3 ′-dimethylamino group from being quaternized with the methylatingagent; eliminating in any desired sequence the R ¹ , R ² , and R ³groups, wherein the elimination of R ² and R ³ is performed by treatmentwith tetrabutyl ammoniumfluoride in tetrahydrofuran; and then,deoximating with a deoximating agent.
 5. A process for preparing6-O-methylerythromycin A comprising: performing the steps of claim 1 ;then eliminating in any desired sequence the R¹ , R ² , and R ³ groups;wherein the R ¹ group is eliminated by homogeneous or heterogeneoushydrogenolysis; and wherein the R ² and R ³ groups are eliminated bytreatment with an acid in an alcohol or with tetrabutyl ammoniumfluoride; and then deoximating with a deoximating agent.
 6. The processof claim 5, wehrein the elimination of R¹ is performed by homogeneoushydrogenolysis.
 7. The process of claim 5, wherein the elimination of R¹is performed by heterogeneous hydrogenolysis.
 8. The process of claim 5,wherein the elimination of R² and R ³ is performed by treatment withacid in an alcohol.
 9. The process of claim 5, wherein the eliminationof R² and R ³ is performed by treatment with tetrabutyl ammoniumfluoride.
 10. A process for preparing 6-O-methylerythromycin Acomprising: performing the steps of claim 1 ; then eliminating in anydesired sequence the R ¹ , R ² , and R ³ groups; wherein the R ¹ groupis eliminated by homogeneous or heterogeneous hydrogenylysis; andwherein the R ² and R ³ groups are eliminated by treatment with an acidin an alcohol or with tetrabutyl ammonium fluoride; and then deoximatingby using sodium hydrogen sulfite, titanium trichloride-ammonium acetate,sodium nitrate-hydrochloric acid, or sodium hydrosulfite.
 11. Theprocess of claim 10, wherein the elimination of R¹ is performed byhomogeneous hydrogenolysis.
 12. The process of claim 10, wherein theelmination of R¹ is performed by hetergeneous hydrogenolysis.
 13. Theprocess of claim 10, wherein the elimination of R² and R ³ is performedby treatment with acid in an alcohol.
 14. The process of claim 10,wherein the elimination of R² and R ³ is performed by treatment withtetrabutyl ammonium fluoride.
 15. The process of claim 10, wherein thedeoximation is performed by using sodium hydroen sulfite.
 16. Theprocess of claim 10, wherein the deoximation is performed by usingtitanium trichloride-ammonium acetate.
 17. The process of claim 10,wherein the deoximation is performed by using sodiumnitrate-hydrochloric acid.
 18. The process of claim 10, wherein thedeoximation is performed by using sodium hydrosulfite.